Method and device for treating myocardial ischemia

ABSTRACT

A method and device for treating myocardial ischemia are described in which the stress experienced by a myocardial region identified as vulnerable to becoming ischemic is varied with pre-excitation pacing. In an unloading mode, pacing is applied in proximity to the vulnerable region to reduce stress and the metabolic demand of the region. In a loading mode, pacing is applied to a region remote from the vulnerable region in order to produce a conditioning effect.

RELATED CASES

This application is related to U.S. Pat. Nos. 6,628,988, 6,973,349,6,915,160, and 6,965,797 and to U.S. patent application Ser. Nos.11/427,517, filed on Jun. 29, 2006 and 11/541,837, filed on Oct. 2,2006, all of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention pertains to cardiac rhythm management devices such aspacemakers and other implantable devices.

BACKGROUND

Myocardial ischemia refers to a condition in which the blood supply to aregion of myocardium (i.e., heart muscle) becomes so compromised thatthe region is not supplied with adequate oxygen for oxidativemetabolism. Ischemia, as opposed to hypoxia without any reduction inperfusion, is also accompanied by reduced removal of metabolicby-products. The heart is an aerobic organ that generates energy almostexclusively from the oxidation of substrates with oxygen delivered bythe blood. It can develop only a small oxygen debt and is thereforeextremely sensitive to disruptions in blood supply. Myocardial ischemiaoccurs when there is an imbalance between oxygen supply and demand as aresult of increased myocardial oxygen demand, reduced myocardial oxygensupply, or both. Myocardial ischemia causes many patients to experiencechest pain or discomfort, referred to as angina pectoris. Anginapectoris can serve as a useful warning of insufficient myocardialperfusion that can lead to the more serious situation such as a heartattack or cardiac arrhythmia.

Coronary artery disease (CAD) occurs when the coronary arteries thatsupply blood to the myocardium become hardened and narrowed due to thebuildup of atherosclerotic plaque. An atherosclerotic plaque is the siteof an inflammatory reaction within the wall of an artery and is made upof a core containing lipid and inflammatory cells surrounded by aconnective tissue capsule. A myocardial infarction (MI), or heartattack, occurs when atherosclerotic plaque within a coronary arteryruptures and leads to the clotting of blood (thrombosis) within theartery by exposing the highly thrombogenic lipid core of the plaque tothe blood. The complete or nearly complete obstruction to coronary bloodflow can damage a substantial area of heart tissue and cause suddendeath, usually due to an abnormal heart rhythm that prevents effectivepumping.

In the presence of coronary obstruction due to CAD, an increase inmyocardial oxygen requirements brought about by, for example, physicalexertion or emotional distress, can cause a temporary imbalance inoxygen supply and demand. Such demand ischemia can cause what is calledexertional anginal or chronic stable angina. In other situations, animbalance can occur acutely due to a sudden reduction in blood flow,sometimes referred to as supply ischemia. An acute blood flow disruptionmay be secondary to a coronary vasospasm, causing what is calledunstable angina. As noted above, an acute blood flow disruption can alsoresult from coronary thrombosis, causing an MI. Myocardial ischemiaoften results from both an increase in oxygen demand and a reduction insupply.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the physical configuration of an exemplary pacingdevice.

FIG. 2 shows the components of an exemplary device.

FIG. 3 is a block diagram of the electronic circuitry of an exemplarydevice.

FIG. 4 illustrates an exemplary algorithm for switching between a normalmode and vulnerable region unloading and loading modes.

FIG. 5 illustrates an exemplary algorithm for dynamically varying an AVdelay interval when delivering pre-excitation pacing.

DETAILED DESCRIPTION

Myocardial ischemia is usually treated with pharmacological agents thatact to either increase myocardial perfusion or reduce myocardial oxygendemand. Surgical revascularization procedures may also be performed toincrease blood supply. Described herein is an alternative interventionfor treating myocardial ischemia that employs appropriately timed andlocated pacing pulses such as may be delivered by an implantable pacingdevice.

Mechanical Effects of Pacing Therapy

When the ventricles are stimulated to contract by a pacing pulse appliedthrough an electrode located at a particular pacing site, the excitationspreads from the pacing site by conduction through the myocardium. Thisis different from the normal physiological situation, where the spreadof excitation to the ventricles from the AV node makes use of theheart's specialized conduction system made up of Purkinje fibers whichallows a rapid and synchronous excitation of the entire ventricularmyocardium. The excitation resulting from a pacing pulse, on the otherhand, produces a relatively asynchronous contraction due to the slowervelocity at which excitation is conducted from the pacing site to therest of the myocardium. Regions of the myocardium located more distallyfrom the pacing site are thus excited later than regions proximal to thepacing site as compared with an intrinsic contraction. As explainedbelow, this results in a re-distribution of myocardial wall stress.

The degree of tension on a muscle fiber before it contracts is termedthe preload, while the degree of tension on a muscle fiber as itcontracts is termed the afterload. Increasing the preload stretches amuscle fiber and also increases its maximum tension and velocity ofshortening during contraction. With respect to the heart, the preload ofa particular myocardial region is the myocardial wall stress at the endof diastole due to end-diastolic pressure and the forces applied byadjacent regions. The afterload of a myocardial region is the myocardialwall stress during systole due to the pressure load that the heart mustpump against. When a myocardial region contracts late relative to otherregions, the contraction of those other regions stretches the latercontracting region and increases its preloading, thus causing anincrease in the contractile force generated by the region. Conversely, amyocardial region that contracts earlier relative to other regionsexperiences decreased preloading and generates less contractile force.Because pressure within the ventricles rises rapidly from a diastolic toa systolic value as blood is pumped out into the aorta and pulmonaryarteries, the parts of the ventricles that contract earlier duringsystole do so against a lower afterload than do parts of the ventriclescontracting later. Delivery of a pacing pulse to a ventricular regionmakes that region contract earlier than other parts of the ventricle.The paced region will therefore be subjected to both a decreased preloadand afterload which decreases the mechanical stress experienced by theregion relative to other regions during systolic contraction. A regionremote from the paced region on the other hand, will experienceincreased mechanical stress.

Pre-Excitation Pacing to Treat Myocardial Ischemia

All but a small fraction of the total amount of oxygen consumed by themyocardium is for the purpose of active muscular contraction duringsystole, and the oxygen demand of a particular myocardial regionincreases with increasing systolic wall stress. Causing a particularmyocardial region to contract earlier relative to other regions willthus lessen its metabolic demands and the degree of any ischemia thatmay be present. In order to cause early contraction and lessened stressto a myocardial region vulnerable to becoming ischemic,electro-stimulatory pacing pulses may be delivered to one or more sitesin or around the vulnerable region in a manner that pre-excites thosesites relative to the rest of the ventricle and mechanically unloads thevulnerable region. Pre-excitation pacing therapy to unload a vulnerableregion may be implemented by pacing the ventricles at a single site inproximity to the vulnerable region or by pacing at multiple ventricularsites in such proximity. In the latter case, the pacing pulses may bedelivered to the multiple sites simultaneously or in a defined pulseoutput sequence. The single-site or multiple site pacing may beperformed in accordance with a bradycardia pacing algorithm such as aninhibited demand mode or a triggered mode.

As described below, an implantable cardiac pacing device may beconfigured with one or more pacing electrodes disposed at apre-excitation pacing site(s) in proximity to the vulnerable region. Thedevice may then be programmed to operate in a vulnerable regionunloading mode that delivers pre-excitation pacing pulses to thevulnerable region in accordance with a programmed pacing mode. Thepre-excitation pacing relieves stress on the vulnerable region andreduces any ischemia that may be present by decreasing the metabolicdemand of the region. The device may be programmed to operate in thevulnerable region unloading mode continuously or intermittently. In thelatter case, the device may revert to a normal mode when the vulnerableregion unloading mode terminates that may include any type of pacing(e.g., bradycardia or cardiac resynchronization pacing) or no pacing atall. The device may then switch from the normal mode to the vulnerableregion unloading mode in accordance with one or more entry conditionssuch as: 1) actuation of a patient-operated switch that the patient mayoperate when angina occurs, 2) receipt of a telemetry command toinitiate the mode, and 3) detection of the presence of myocardialischemia by the device in accordance with a sensed variable that iscorrelated with the presence of myocardial ischemia. Examples of sensedvariables reflective of myocardial ischemia include features derivedfrom sensed cardiac electrical activity and/or, in a patient with demandischemia, variables related to exertion level such as heart rate, minuteventilation, and activity level. The vulnerable region unloading modemay also be caused to terminate upon detection of one or more specifiedevents or conditions, referred to as exit conditions. Such exitconditions could include, for example, non-detection of the presence ofmyocardial ischemia, a lapsed time interval, actuation of apatient-operated switch, and receipt of a telemetry command to terminatethe mode.

In order for pre-excitation pacing to cause early contraction of a pacedregion relative to other regions, the latter regions should not beexcited by intrinsic excitation conducted from the AV node. When thevulnerable region unloading mode delivers pre-excitation pacing in anatrial tracking or AV sequential pacing mode, the AV delay intervalshould be selected to be short enough relative to the patient'sintrinsic AV interval that depolarization spreads beyond the pre-excitedsite and excites the rest of the myocardium without interference fromintrinsic excitation. The shorter the AV delay interval is relative tothe patient's intrinsic AV interval, the more the paced site ispre-excited. In one embodiment, the device is configured to dynamicallyshorten the AV delay interval in the vulnerable region unloading mode inaccordance with a sensed variable that is correlated with the presenceof myocardial ischemia such as described above in order to provide morestress reducing pre-excitation as it is needed. For example, the AVdelay interval could be shortened in accordance with measured heart rateor exertion level. Shortening the AV delay interval in this manner alsocompensates for the physiological shortening of the patient's intrinsicAV interval that occurs with increasing heart rate.

Another use of pre-excitation pacing in the treatment of myocardialischemia is to intentionally stress a vulnerable region by pacing at asite(s) remote from the vulnerable region. As described above, suchpacing causes increased mechanical stress to the vulnerable region bydelaying its contraction during systole relative to other regions.Intermittently stressing the vulnerable region causes a low level ofmyocardial ischemia in the region in a patient with demand ischemia,thereby promoting angiogenesis and possibly pre-conditioning thevulnerable region to better withstand the effects of a subsequentischemic episode. Accordingly, the device may be configured tointermittently switch from a normal mode or vulnerable region unloadingmode to a vulnerable region loading mode that delivers pre-excitationpacing to a site(s) remotely located from the vulnerable region. Suchpre-excitation pacing may be delivered with a shortened or dynamicallyshortened AV delay interval as described above to facilitate thepre-excitation. Intermittent switching to the vulnerable region loadingmode may be controlled in accordance with one or more entry conditionsand one or more exit conditions, where such entry and exit conditionsmay include lapsed time intervals, heart rate, activity level asmeasured by an accelerometer, and minute ventilation. Since thevulnerable region loading mode is designed to produce low levelmyocardial ischemia, it is desirable for it to only be employed when thepatient is at rest and not experiencing an ischemic episode by reason ofeither increased metabolic demand or decreased blood supply. Forexample, an entry condition for entering the vulnerable region loadingmode could be the measured heart rate and/or exertion level being belowsome specified threshold value, and an exit condition for terminatingthe vulnerable region loading mode could be the measured heart rateand/or exertion level being above some specified threshold value.Additional entry and exit conditions could be lapsed time intervalsbased upon a defined schedule so that the vulnerable region loading modeis only entered at certain times of the day and/or is limited induration.

Exemplary Implantable Device

FIG. 1 shows an implantable cardiac device 100 for deliveringpre-excitation therapy to a vulnerable region as well as possibly othertypes of pacing therapy. Implantable pacing devices are typically placedsubcutaneously or submuscularly in a patient's chest with leads threadedintravenously into the heart to connect the device to electrodesdisposed within a heart chamber that are used for sensing and/or pacingof the chamber. Electrodes may also be positioned on the epicardium byvarious means. A programmable electronic controller causes the pacingpulses to be output in response to lapsed time intervals and/or sensedelectrical activity (i.e., intrinsic heart beats not as a result of apacing pulse). The device senses intrinsic cardiac electrical activitythrough one or more sensing channels, each of which incorporates one ormore of the electrodes. In order to excite myocardial tissue in theabsence of an intrinsic beat, pacing pulses with energy above a certainthreshold are delivered to one or more pacing sites through one or morepacing channels, each of which incorporates one or more of theelectrodes. FIG. 1 shows the exemplary device having two leads 200 and300, each of which is a multi-polar (i.e., multi-electrode) lead havingelectrodes 201-202 and 301-304, respectively. The electrodes 201-202 aredisposed in the right ventricle in order to excite or sense rightventricular and/or septal regions, while the electrodes 301-304 aredisposed in the coronary sinus in order to excite or sense regions ofthe left ventricle. If a vulnerable region VR were located in the apicalregion of the left ventricle, pre-excitation pacing in a vulnerableregion unloading mode could be delivered via electrodes 303 and 304 in abipolar pacing configuration to unload the vulnerable region. Suchpre-excitation pacing could be delivered, for example, as leftventricular-only pacing or as biventricular pacing with an offset suchthat the left ventricle is paced before the right. Conversely, in avulnerable region loading mode, pre-excitation pacing could be deliveredvia electrodes 201 and 202 in a right ventricle-only pacing mode orelectrodes 301 and 302 in a left ventricle-only or biventricular pacingmode in order to pre-excite a myocardial region remote from thevulnerable region. Other embodiments may use any number of electrodes inthe form of unipolar and/or multi-polar leads in order to excitedifferent myocardial sites. As explained below, once the device andleads are implanted, the pacing and/or sensing channels of the devicemay be configured with selected ones of the multiple electrodes in orderto selectively pace or sense a particular myocardial site(s).

FIG. 2 shows the components of the implantable device 100 in more detailas well as an exemplary monitoring/programming system. The implantabledevice 100 includes a hermetically sealed housing 130 that is placedsubcutaneously or submuscularly in a patient's chest. The housing 130may be formed from a conductive metal, such as titanium, and may serveas an electrode for delivering electrical stimulation or sensing in aunipolar configuration. A header 140, which may be formed of aninsulating material, is mounted on the housing 130 for receiving leads200 and 300 which may be then electrically connected to pulse generationcircuitry and/or sensing circuitry. Contained within the housing 130 isthe electronic circuitry 132 for providing the functionality to thedevice as described herein which may include a power supply, sensingcircuitry, pulse generation circuitry, a programmable electroniccontroller for controlling the operation of the device, and a telemetrytransceiver capable of communicating with an external programmer or aremote monitoring device 190. An external programmer wirelesslycommunicates with the device 100 and enables a clinician to receive dataand modify the programming of the controller. A remote monitoring devicealso communicates via telemetry with the device 100 and may be furtherinterfaced to a network 195 (e.g., an internet connection) forcommunicating with a patient management server 196 that allows clinicalpersonnel at remote locations to receive data from the remote monitoringdevice as well as issue commands. The controller may be programmed suchwhen particular conditions are detected by the monitoring circuitry(such as when a measured parameter exceeds or falls below a specifiedlimit value), the device transmits an alarm message to the remotemonitoring device and to the patient management server to alert clinicalpersonnel.

A block diagram of the circuitry 132 is illustrated in FIG. 3. A battery22 supplies power to the circuitry. The controller 10 controls theoverall operation of the device in accordance with programmedinstructions and/or circuit configurations. The controller may beimplemented as a microprocessor-based controller and include amicroprocessor and memory for data and program storage, implemented withdedicated hardware components such as ASICs (e.g., finite statemachines), or implemented as a combination thereof. The controller alsoincludes timing circuitry such as external clocks for implementingtimers used to measure lapsed intervals and schedule events. As the termis used herein, the programming of the controller refers to either codeexecuted by a microprocessor or to specific configurations of hardwarecomponents for performing particular functions. Interfaced to thecontroller are sensing circuitry 30 and pulse generation circuitry 20 bywhich the controller interprets sensing signals and controls thedelivery of paces in accordance with a pacing mode. The sensingcircuitry 30 receives atrial and/or ventricular electrogram signals fromsensing electrodes and includes sensing amplifiers, analog-to-digitalconverters for digitizing sensing signal inputs from the sensingamplifiers, and registers that can be written to for adjusting the gainand threshold values of the sensing amplifiers. The pulse generationcircuitry 20 delivers pacing pulses to pacing electrodes disposed in theheart and includes capacitive discharge pulse generators, registers forcontrolling the pulse generators, and registers for adjusting pacingparameters such as pulse energy (e.g., pulse amplitude and width). Thedevice allows adjustment of the pacing pulse energy in order to ensurecapture of myocardial tissue (i.e., initiating of a propagating actionpotential) by a pacing pulse. Myocardial sites in proximity to anischemic region may be less excitable than normal and require anincreased pacing energy in order to achieve capture. Pacing pulseenergies for pre-exciting ischemic regions may be adjusted byprogramming the device via the telemetry interface in accordance withelectrophysiological testing to determine an appropriate pacing pulseenergy or may be adjusted automatically with an autocapture functionsuch as described in U.S. patent application Ser. No. 11/427,517, filedon Jun. 29, 2006. The pulse generation circuitry may also include ashocking pulse generator for delivering a defibrillation/cardioversionshock via a shock electrode upon detection of a tachyarrhythmia. Atelemetry transceiver 80 is interfaced to the controller which enablesthe controller to communicate with an external programmer and/or aremote monitoring unit. A magnetically or tactilely actuated switch 24is also shown as interfaced to the controller to allow the patient tosignal certain conditions or events to the implantable device.

A pacing channel is made up of a pulse generator connected to anelectrode, while a sensing channel is made up of a sense amplifierconnected to an electrode. Shown in the figure are electrodes 40 ₁through 40 _(N) where N is some integer. The electrodes may be on thesame or different leads and are electrically connected to a MOS switchmatrix 70. The switch matrix 70 is controlled by the controller and isused to switch selected electrodes to the input of a sense amplifier orto the output of a pulse generator in order to configure a sensing orpacing channel, respectively. The device may be equipped with any numberof pulse generators, amplifiers, and electrodes that may be combinedarbitrarily to form sensing or pacing channels. The switch matrix 70allows selected ones of the available implanted electrodes to beincorporated into sensing and/or pacing channels in either unipolar orbipolar configurations. A bipolar sensing or pacing configuration refersto the sensing of a potential or output of a pacing pulse between twoclosely spaced electrodes, where the two electrodes are usually on thesame lead (e.g., a ring and tip electrode of a bipolar lead or twoselected electrodes of a multi-polar lead). A unipolar sensing or pacingconfiguration is where the potential sensed or the pacing pulse outputby an electrode is referenced to the conductive device housing oranother distant electrode.

The device illustrated in FIG. 3 may be configured with multiple sensingand/or pacing channels that may be either atrial or ventricular channelsdepending upon the location of the electrode. The device is thereforecapable of delivering single-site or multiple site ventricularpre-excitation pacing for purposes of stress reduction/augmentation aswell as conventional pacing. The switch matrix allows particularmyocardial sites to be pre-excited for purposes of stress reduction oraugmentation by selecting the appropriately disposed electrode(s) to beincorporated into a pacing channel used to deliver pre-excitationpacing. Configuration of pacing and sensing channels may be performedvia an external programmer communicating through the telemetry interfaceas well as automatically by the device when switching to or fromdifferent pacing modes.

Pre-excitation pacing may be delivered as single-site pacing,biventricular pacing where one of the ventricles is pre-excited relativeto the other as determined by a programmed biventricular offsetinterval, or delivered as multi-site ventricular pacing. In the casewhere the pre-excitation pacing is delivered at multiple sites, thesites may be paced simultaneously or in accordance with a particularpulse output sequence that specifies the order and timing in which thesites are to be paced during a single beat. When an electrogram signalin an atrial or ventricular sensing channel exceeds a specifiedthreshold, the controller detects an atrial or ventricular sense,respectively, which pacing algorithms may employ to trigger or inhibitpacing. The controller is capable of operating the device in a number ofprogrammed modes where a programmed mode defines how pacing pulses areoutput in response to sensed events and expiration of time intervals.Pre-excitation pacing of one or more ventricular sites in proximity to,or remote from, a vulnerable region may be delivered in conjunction witha bradycardia pacing mode, which refers to a pacing algorithm thatenforces a certain minimum heart rate, and may include or not includepacing pulses delivered to the atria or ventricles for other purposes(e.g., treatment of bradycardia). Inhibited demand bradycardia pacingmodes utilize escape intervals to control pacing in accordance withsensed intrinsic activity. In an inhibited demand ventricular pacingmode, the ventricle is paced during a cardiac cycle only afterexpiration of a defined escape interval during which no intrinsic beatby the chamber is detected. For example, a ventricular escape intervalcan be defined between ventricular events so as to be restarted witheach ventricular sense or pace, referred to as a lower rate interval(LRI). The inverse of this escape interval is the minimum rate at whichthe pacemaker will allow the ventricles to beat, sometimes referred toas the lower rate limit (LRL). Paces may also be delivered in arate-adaptive pacing mode where the escape intervals are modified inaccordance with a measured exertion level such as with accelerometer 26or minute ventilation sensor 25. In atrial tracking and AV sequentialpacing modes, another ventricular escape interval is defined betweenatrial and ventricular events, referred to as the atrio-ventricular orAV interval. The atrio-ventricular interval is triggered by an atrialsense or pace and stopped by a ventricular sense or pace. A ventricularpace is delivered upon expiration of the atrio-ventricular interval ifno ventricular sense occurs before the expiration. Deliveringpre-excitation pacing with a shortened AV interval relative to thepatient's intrinsic AV interval (e.g., 30-80% of the intrinsic interval)facilitates pre-excitation by allowing the depolarization to spreadbeyond the pre-excited site and excite the rest of the myocardiumwithout interference from intrinsic excitation.

The implantable device may also incorporate autocapture, autothreshold,and reconfiguration functionality described in U.S. patent applicationSer. No. 11/427,517, filed on Jun. 29, 2006, which are especially usefulfor the delivery of pre-excitation pacing to a vulnerable region becausethe excitability characteristics of a vulnerable region may change overtime. The device thus may be configured to automatically adjustpre-excitation pacing pulse energies and/or pre-excitation pacing sitesin order maintain capture by the pre-excitation pacing pulses. In orderto determine whether or not a pacing pulse has achieved capture, acapture verification test is performed in which an evoked response tothe pre-excitation pacing pulse detected. An evoked response sensingchannel is configured using the switch matrix to select an appropriateelectrode which may be the same electrode used to deliver the pacingpulse or another electrode disposed near the pacing site. Verifyingcapture by the pacing pulse involves comparing the evoked responseelectrogram signal following the pace to a predetermined threshold,which may be performed by the controller or other dedicated circuitry.If the evoked response electrogram signal exceeds the threshold, captureis presumed to have occurred. Upon detection of capture failure, or inorder to determine a minimum pacing energy, an autothreshold proceduremay be performed by the device in which a minimum pacing threshold isdetermined. The pacing pulse energy is then adjusted accordingly tomatch the determined minimum pacing threshold with an appropriate safetymargin. Automatic pacing electrode reconfiguration, entailing changingpacing sites until one is found for which capture is possible, may beperformed upon detection of a loss of capture and when the autocapturefunction is unable to adjust the pacing pulse energy for a particularpacing site to a level adequate to regain capture using the availablepacing pulse amplitudes and widths supported by the device. The pacingelectrode reconfiguration algorithm can also be performed periodicallyor upon command. Such reconfiguration may be performed in accordancewith a preprogrammed ordered list of the available pacing electrodesthat lists the electrodes in a preferred order of use as determined byclinical testing in order to ensure that the reconfiguration algorithmselects the most optimum pacing location for pre-excitation pacing.

Detection of Myocardial Ischemia

When the blood supply to a region of the myocardium is compromised, thesupply of oxygen and other nutrients can become inadequate for enablingthe metabolic processes of the cardiac muscle cells to maintain theirnormal polarized state. An ischemic region of the heart thereforebecomes abnormally depolarized during at least part of the cardiac cycleand causes a current to flow between the ischemic region and thenormally polarized regions of the heart, referred to as a current ofinjury. A current of injury may be produced by an infarcted region thatbecomes permanently depolarized or by an ischemic region that remainsabnormally depolarized during all or part of the cardiac cycle. Ischemiaand infarction can also affect the magnitude of depolarization and thevelocity at which it travels through the myocardium. All of theseeffects result in abnormal changes in the electrical potentials producedby cardiac excitation as reflected by either a surface electrocardiogramor an intracardiac electrogram. The device may therefore be configuredto detect the presence of myocardial ischemia from one or more sensedvariables related to cardiac electrical activity.

The device may be configured to detect cardiac ischemia from amorphology analysis of an electrogram collected during an intrinsic or apaced beat, the latter sometimes referred to as an evoked response. Asaforesaid, a current of injury results in an abnormal change in theelectrical potentials measured by an intracardiac electrogram. If theabnormal depolarization in the ventricles lasts for the entire cardiaccycle, a zero potential is measured only when the rest of theventricular myocardium has depolarized, which corresponds to the timebetween the end of the QRS complex and the T wave in an electrogram andis referred to as the ST segment. After repolarization of theventricles, marked by the T wave in an electrogram, the measuredpotential is influenced by the current of injury and becomes shifted,either positively or negatively depending upon the location of theischemic or infarcted region, relative to the ST segment. Traditionally,however, it is the ST segment that is regarded as shifted when anabnormal current of injury is detected by an electrogram orelectrocardiogram. A current injury produced by an ischemic region thatdoes not last for the entire cardiac cycle may only shift part of the STsegment, resulting in an abnormal slope of the segment. A current ofinjury may also be produced when ischemia causes a prolongeddepolarization in a ventricular region which results in an abnormal Twave as the direction of the wave of repolarization is altered. In orderfor the device to detect a change in an electrogram indicative ofischemia, a recorded electrogram is analyzed and compared with areference electrogram, which may either be a complete recordedelectrogram or particular reference values representative of anelectrogram. Because certain patients may always exhibit a current ofinjury in an electrogram (e.g., due to CAD or as a result of electrodeimplantation), the controller may be programmed to detect ischemia bylooking for an increased current of injury in the recorded electrogramas compared with the reference electrogram, where the latter may or maynot exhibit a current of injury. One way to look for an increasedcurrent of injury in the recorded electrogram is to compare the STsegment amplitude and/or slope with the amplitude and slope of areference electrogram. Various digital signal processing techniques maybe employed for the analysis, such as using first and second derivativesto identify the start and end of an ST segment. Other ways of lookingfor a current injury may involve, for example, cross-correlating therecorded and reference electrograms to ascertain their degree ofsimilarity. The electrogram could be implicitly recorded in that case bypassing the electrogram signal through a matched filter thatcross-correlates the signal with a reference electrogram. The ST segmentcould also be integrated, with the result of the integration comparedwith a reference value to determine if an increased current of injury ispresent.

As mentioned previously, other sensed variables may also be indicativeof the presence of myocardial ischemia, especially in patients withexertional angina. The device may therefore be programmed to detect thepresence of myocardial ischemia from sensed variables such as heartrate, activity level, local cardiac motion, local tissue impedance, andminute ventilation, either in addition to or instead of the techniquesdiscussed above based upon cardiac electrical activity. To addspecificity to the detection scheme, for example, the device may beprogrammed to detect myocardial ischemia only when a current of injuryis detected and the patient's heart rate and/or exertion level is abovea specified threshold value.

Exemplary Implementations

In order to provide pre-excitation therapy as described above to amyocardial region vulnerable to becoming ischemic, the region must beidentified anatomically so that one or more pacing electrodes can beplaced in proximity thereto. An area of ischemia can be identified by anumber of means, including ultrasonic imaging, PET scans, thalliumscans, and MRI perfusion scans. Stress testing may be employed to inducemyocardial ischemia in a patient with demand ischemia. A myocardialregion identified as either ischemic or vulnerable to becoming ischemicis deemed to be a vulnerable region that can be mechanically loaded orunloaded with pre-excitation pacing therapy. After implantation andappropriate placement of electrodes, the device may then be programmedto be configured with appropriate sensing and pacing channels to deliverpre-excitation pacing to one or more sites in proximity to, and/orremote from, the identified vulnerable region accordance with aparticular pacing mode.

An exemplary implantable pacing device is equipped with one or moreleads having first and second electrodes that can be placed at differentpacing sites. In an exemplary electrode placement, the first electrodeis disposed near a ventricular region vulnerable to ischemia so that apacing pulse from the first electrode unloads the vulnerable regionduring systole as compared with an intrinsic beat, and the secondelectrode is disposed near a ventricular region remote from thevulnerable region so that a pacing pulse from the second electrode loadsthe vulnerable region during systole as compared with an intrinsic beat.The device may be configured to operate in a vulnerable region unloadingmode that delivers pacing pulses through a pacing channel configuredwith the first electrode and to intermittently operate in a vulnerableregion loading mode that delivers pacing pulses through a pacing channelconfigured with the second electrode.

The device may also be equipped with one or more sensors for sensing avariable that can be correlated with the occurrence of myocardialischemia and programmed to detect the presence or absence of myocardialischemia in accordance with the sensed variable. In various embodiments,the sensor(s) may be a cardiac sensing channel for recordingelectrograms and measuring heart rate, an accelerometer for measuringactivity level or local cardiac motion, an impedance sensor sensitive tolocal changes in tissue impedance that occur during ischemia, and/or aminute ventilation sensor. The device may then be configured tointermittently switch to the vulnerable region loading mode according toa defined schedule but to switch to the vulnerable region loading modeonly if the sensed variable indicates the absence of myocardialischemia. For example, the device may sense the patient's exertion level(e.g., as reflected by heart rate, activity level, and/or minuteventilation) and be configured to intermittently switch to thevulnerable region loading mode but to switch to the vulnerable regionloading mode only if the sensed variable is within a specified range.

The device could also be configured to operate in a normal mode when notoperating in either the vulnerable region unloading or loading modes,where the normal mode may or may not deliver pacing therapy. In oneembodiment, for example, the device is equipped with a third electrodeadapted for disposition near a ventricular region apart from thelocations of the first and second electrodes, and the controller isprogrammed to operate in a normal mode that delivers pacing pulsesthrough a pacing channel configured with the third electrode. Thecontroller is then programmed to switch to the vulnerable regionunloading mode whenever the sensed variable indicates the presence ofmyocardial ischemia and operate intermittently in either the vulnerableregion loading mode or the normal mode whenever the sensed variableindicates the absence of myocardial ischemia. The device could also beconfigured to switch from the normal mode to the vulnerable regionunloading mode if the sensed variable indicates the presence ofmyocardial ischemia. FIG. 4 illustrates an example algorithm that couldbe executed by the controller to switch between the normal mode and thevulnerable region unloading or loading modes. At step A1, the deviceoperates in the normal mode, which may entail delivering some kind ofpacing therapy (e.g., bradycardia or resynchronization pacing) ordelivering no pacing at all. At step A2, the device checks for thepresence of ischemia. If myocardial ischemia is detected, the deviceoperates in the vulnerable region unloading mode at step A3 for as longas the ischemia is present. If myocardial ischemia is not present, thedevice checks to see if it is time to switch to the vulnerable regionloading mode at step A4. If so, the device determines at step A5 if themeasured exertion level is below a specified value that indicates thepatient is at rest. If the patient is at rest, the device operates inthe vulnerable region loading mode at step A6 and remains in that modeuntil a specified duration has elapsed as determined at step A7.

In order to provide atrio-ventricular synchrony, the device may beconfigured to deliver pacing pulses in the vulnerable region unloadingand/or vulnerable region loading modes in accordance with an atrialtracking or AV sequential pacing mode with a specified AV delayinterval. To facilitate pre-excitation in either the unloading orloading mode, the AV delay interval should be set shorter than themeasured intrinsic AV interval so that intrinsic excitation of theventricle does not interfere with excitation from the pre-excitationpacing. For example, the AV delay interval may be set to be between 50and 80% of the measured intrinsic AV interval. In one embodiment, thedevice is configured to measure the patient's intrinsic AV interval andset the AV delay interval automatically in accordance with themeasurement.

The device may also be configured to dynamically adjust the AV delayinterval to compensate for changes in the patient's intrinsic AVinterval and/or adjust the amount of pre-excitation delivered in thevulnerable region unloading and/or loading modes. In this embodiment,the device may configured to adjust the AV delay interval in accordancewith a sensed variable reflective of myocardial ischemia and/or thepatient's exertion level such as heart rate, activity level, and/orminute ventilation. FIG. 5 illustrates an example algorithm that couldbe executed by the controller while delivering pre-excitation pacing inthe vulnerable region unloading or loading modes. At step B1, the devicedelivers pre-excitation pacing with a specified AV delay interval. Atstep B2, the device obtains a measurement of the patient's exertionlevel, which may be an instantaneous or an average measurement. At stepB3, the AV delay interval is computed as a function of the exertionlevel measurement which may be implemented, for example, as a look-uptable. Under normal circumstances, the AV delay interval will bedecreased as the measured exertion level increases and vice-versa. Atstep B4, the AV delay interval is set to the computed value, and areturn is made to step B1 to continue pre-excitation pacing with the newAV delay interval.

In another embodiment, the patient is provided with a means forswitching the device to the vulnerable region loading mode, to thevulnerable region unloading mode upon experiencing symptoms ofmyocardial ischemia, and/or to a normal mode. Such a means, for example,may be a patient-operated switch interfaced to the device controllersuch as a magnetically-actuated or tactilely-actuated switch. Thepatient may also be provided with a means for communicating to thedevice via telemetry, such as from a remote monitor, in order to issue acommand to switch to a selected mode.

The invention has been described in conjunction with the foregoingspecific embodiments. It should be appreciated that those embodimentsmay also be combined in any manner considered to be advantageous. Also,many alternatives, variations, and modifications will be apparent tothose of ordinary skill in the art. Other such alternatives, variations,and modifications are intended to fall within the scope of the followingappended claims.

1. A method, comprising: identifying a vulnerable ventricular region ina patient that is predisposed to becoming ischemic; implanting a cardiacpacing device having first and second electrodes; implanting the firstelectrode near the ventricular region vulnerable to ischemia so that apacing pulse from the first electrode unloads the vulnerable regionduring systole as compared with an intrinsic beat; implanting the secondelectrode near a ventricular region remote from the vulnerable region sothat a pacing pulse from the second electrode loads the vulnerableregion during systole as compared with an intrinsic beat; configuringthe device to operate in a vulnerable region unloading mode thatdelivers pacing pulses through a pacing channel configured with thefirst electrode; and, configuring the device to intermittently operatein a vulnerable region loading mode that delivers pacing pulses througha pacing channel configured with the second electrode.
 2. The method ofclaim 1 further comprising: configuring the device to sense a variablethat can be correlated with the occurrence of myocardial ischemia and todetect the presence or absence of myocardial ischemia in accordance withthe sensed variable; configuring the device to intermittently switch tothe vulnerable region loading mode according to a defined schedule butto switch to the vulnerable region loading mode only if the sensedvariable indicates the absence of myocardial ischemia.
 3. The method ofclaim 1 further comprising: configuring the device to sense a variablerelated to the patient's exertion level; configuring the device tointermittently switch to the vulnerable region loading mode but toswitch to the vulnerable region loading mode only if the sensed variableis within a specified range.
 4. The method of claim 1 further comprisingconfiguring the device to sense a variable that can be correlated withthe occurrence of myocardial ischemia and to detect the presence orabsence of myocardial ischemia in accordance with the sensed variable;and, configuring the device to switch from a normal mode to thevulnerable region unloading mode if the sensed variable indicates thepresence of myocardial ischemia, wherein the normal mode may or may notdeliver pacing therapy.
 5. The method of claim 1 further comprising:measuring the patient's intrinsic AV interval; configuring the device todeliver pacing pulses in accordance with an atrial tracking or AVsequential pacing mode with a specified AV delay interval in thevulnerable region unloading and vulnerable region loading modes; and,setting the AV delay interval to be shorter than the measured intrinsicAV interval.
 6. The method of claim 5 further comprising setting the AVdelay interval to be between 30 and 80% of the measured intrinsic AVinterval.
 7. The method of claim 1 further comprising: configuring thedevice to sense a variable related to the patient's exertion level;configuring the device to deliver pacing pulses in accordance with anatrial tracking or AV sequential pacing mode with a specified AV delayinterval in the vulnerable region unloading mode; and, configuring thedevice to dynamically adjust the AV delay interval in accordance withthe sensed variable.
 8. The method of claim 1 further comprising:configuring the device to sense a variable related to the patient'sexertion level; configuring the device to deliver pacing pulses inaccordance with an atrial tracking or AV sequential pacing mode with aspecified AV delay interval in the vulnerable region loading mode; and,configuring the device to dynamically adjust the AV delay interval inaccordance with the sensed variable.
 9. The method of claim 1 furthercomprising providing the patient with a means for switching the deviceto the vulnerable region loading mode.
 10. The method of claim 1 furthercomprising providing the patient with a means for switching the deviceto the vulnerable region unloading mode upon experiencing symptoms ofmyocardial ischemia.
 11. A cardiac device, comprising: an implantablehousing for containing electronic circuitry; a sensor for sensing avariable that can be correlated with the occurrence of myocardialischemia in a patient; a first electrode adapted for disposition near aventricular region vulnerable to ischemia; a second electrode adaptedfor disposition near a ventricular region remote from the vulnerableregion; a pulse generator for outputting pacing pulses; a controllerprogrammed to deliver pacing pulses through a pacing channel inaccordance with a programmed pacing mode; wherein the controller isprogrammed to detect the presence or absence of myocardial ischemia inaccordance with the sensed variable; wherein the controller isprogrammed to operate in a vulnerable region unloading mode thatdelivers pacing pulses through a pacing channel configured with thefirst electrode or a vulnerable region loading mode that delivers pacingpulses through a pacing channel configured with the second electrode;and, wherein the controller is programmed to operate in the vulnerableregion unloading mode if the sensed variable indicates the presence ofmyocardial ischemia and operate in the vulnerable region loading mode ifthe sensed variable indicates the absence of myocardial ischemia. 12.The device of claim 11 wherein the sensor is a cardiac sensing channelfor sensing cardiac electrical activity, the sensed variable is anelectrogram and wherein the controller is programmed to detect thepresence of myocardial ischemia if a current of injury is found in theelectrogram.
 13. The device of claim 11 wherein the sensor is a cardiacsensing channel for sensing cardiac electrical activity and the sensedvariable is heart rate.
 14. The device of claim 11 wherein the sensor isan accelerometer for measuring the patient's activity level.
 15. Thedevice of claim 11 wherein the sensor is a minute ventilation sensor.16. The device of claim 11 wherein the controller is programmed to:switch to the vulnerable region unloading mode whenever the sensedvariable indicates the presence of myocardial ischemia; and, switch tothe vulnerable region loading mode whenever the sensed variableindicates the absence of myocardial ischemia.
 17. The device of claim 11wherein the controller is programmed to intermittently switch to thevulnerable region loading mode if the sensed variable indicates theabsence of myocardial ischemia.
 18. The device of claim 11 furthercomprising: a third electrode adapted for disposition near a ventricularregion apart from the locations of the first and second electrodes;wherein the controller is programmed to operate in a normal mode thatdelivers pacing pulses through a pacing channel configured with thethird electrode; and, wherein the controller is programmed to: switch tothe vulnerable region unloading mode whenever the sensed variableindicates the presence of myocardial ischemia; and, operateintermittently in either the vulnerable region loading mode or thenormal mode whenever the sensed variable indicates the absence ofmyocardial ischemia.
 19. The device of claim 11 wherein the controlleris programmed to operate in the vulnerable region loading mode accordingto a defined schedule where operation in the vulnerable region loadingmode is permitted only if the sensed variable indicates the absence ofmyocardial ischemia.
 20. The device of claim 11 further comprising apatient-actuated switch and wherein the controller is programmed toswitch to the vulnerable region unloading mode if the patient-actuatedswitch is actuated.